Anti-inflammatory salicylic acid derivatives

ABSTRACT

SALICYLIC ACID DERIVATIVES AND THEIR NON-TOXIC PHARMACEUTICALLY ACCEPTABLE SALTS, ESTERS AND AMIDES ARE CLAIMED. ALSO ENCOMPASSED IS THE TREATMENT OF INFLAMMATION WITH SAID DERIVATIVES.

United States Patent Ofice 3,657,432 Patented Apr. 18, 1972 3,657,432ANTI-INFLAMMATORY SALICYLIC ACID DERIVATIVES Tsung-Ying Shen, Gordon L.Walford, and Bruce E. Witzel, Westfield, N.J., assignors to Merck & Co.,Inc.,

Rahway, NJ.

No Drawing. Continuation-impart of application Ser. No. 836,622, June25, 1969. This application Apr. 20, 1970, Ser. No. 30,323

Int. Cl. A61u 27/00 U.S. Cl. 424-232 4 Claims ABSTRACT OF THE DISCLOSURESalicylic acid derivatives and their non-toxic pharmaceuticallyacceptable salts, esters and amides are claimed. Also encompassed is thetreatment of inflammation with said derivatives.

CROSS REFERENCES TO RELATE APPLICATIONS This application is acontinuation-in-part of our copending US. application Ser. No. 836,622,filed June 25, 1969.

This invention relates to novel anti-inflammatory com.- pounds. Moreparticularly, it relates to acids of the formula:

and the esters, amides, anhydrides and non-toxic pharmaceuticallyacceptable salts thereof in which,

A is S, So, S 0,

I N-acety1 NH, NR Y is CH N, 1 1 i H S or 0; wherein R is lower alkyl Ris H; acyl (preferably lower acyl such as formyl, acetyl, propionyl,butyryl etc); alkyl (preferably lower alkyl such as methyl, ethyl,propyl, isopropyl, butyl, pentyl, etc.); alkoxycarbonyl (for examplemethoxycarbonyl, ethoxycarbonyl, butoxycarbonyl, hexoxycarbonyl, etc.).

R may be hydrogen, halogen (such as chloro, bromo, fluoro, or iodo,preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl suchas trifiuoromethyl, etc.), alkyl (preferably loweralkyl, such as methyl,ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (for example,cyclobtuyl, cyclopentyl, cyclopropyl, cyclohexyl and cycloheptyl), oralkoxy (preferably loweralkoxy such as methoxy, ethoxy, isopropoxy orbutoxy etc.);

X may be hydrogen, alkyl, (preferably loweralkyl, such 'as methyl,ethyl, propyl, isopropyl, butyl, pentyl, etc.), hydroxy, alkoxy(preferably loweralkoxy such as methoxy, ethoxy, isopropoxy or butoxyetc.), acyloxy (such as benzoyloxy, acetoxy or propionoxy), halogen(such as chloro, bromo, fluoro or iodo, preferably fluoro or chloro),haloalkyl (preferably haloloweralkyl such as trifluoromethyl, etc.),nitro, amino, alkylamino (preferably loweralkylamino such asmethylamino, propylamino, pentylamino, etc.), diloweralkylamino(dimethylamino, dibutylamino, propylpentylamino, etc.), acylamino(preferably loweracylamino such as formylamino, acetylamino,propionylamino, =butyrylamino, etc.), mercapto, alkylmercapto(preferably loweralkylm-ercapto such as methylmercapto, ethylmercapto,etc.), alkylsulfinyl (preferably loweralkylsulfinyl such asmethylsulfinyl, ethylsulfinyl, butylsulfinyl, etc.), alkylsulfonyl(preferably loweralkylsulfonyl such as methylsulfony, ethylsulfonyl,butylsulfonyl, etc.), sulfonamido, sulfonylamido, aminoalkyl,alkylaminoalkyl (preferably loweralkylaminoloweralkyl such asmethylaminomethyl, ethylaminomethyl, etc., (such as dimethylaminomethyl,methylethylaminomethyl); hydroxyalkyl (preferably hydroxyloweralkyl suchas hydroxymethyl, hydroxyethyl, hydroxypropyl, acyl-aminomethyl,alkoxyalkyl (preferably lowerallcoxyloweralkyl such as methoxymethyl,methoxyethyl, ethoxyethyl, ethoxypropyl, etc.), mercaptoalkyl(preferably mercaptoloweralkyl such as mercaptomethyl, mercaptoethyl,etc.), alkylmercaptoalkyl (preferably loweralkylmercaptoloweralkyl suchas methylmercaptomethyl, ethylmercaptoethyl, ethylmercaptopropyl, etc.),cyano, carboxy, car- :boalkoxy (carbomethyl, canboethoxy etc.),carbamoyl, aryl (such as phenyl, halophenyl, tolyl, salicyl), aralkylsuch as benzyl, aryloxy, and, aralkoxy and acyl (preferably lower acylsuch as formyl, acetyl and butyryl etc.).

The preferred class of acids of the salicylic configuration where the 0Ris ortho to the COOH; the bridging member A is attached to the 4 or 5position of the henzene ring and to the 2 or 3 position of the fivemembered ring above.

The acid derivatives of the above description possess a high degree ofanti-inflammatory activity. They are of value in the treatment ofarthritic and dermatological disorders or like conditions responsive toanti-inflammatory drugs. Included within this category are diseases suchas rheumatoid arthritis, osteo arthritis, gout, infectious arthritis andrheumatic fever. The acid derivatives also possess a useful degree ofanalgesic, anti-pyretic, diuretic, anti-fibrinolytic and hypo-glycemicactivity and when used for these utilities the same dosage ranges andconditions described subsequently for the treatment of inflammation willapply.

For these purposes the compounds of the invention may be administeredorally, topically, parenterally or rectally in formulations containingconventional non-toxic pharmaceutically acceptable carriers, adjuvantsand vehicles. In addition to the treatment of warm-blooded animals suchas mice, rats, etc., the compounds of the invention are effective in thetreatment of humans.

The non-toxic pharmaceutical carriers indicated above include eithersolids or liquids. Exemplary of solid carriers are lactose, corn starch,gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba,sucrose, agar, pectin, Cab-O-Sil, and acacia. Exemplary of liquidcarriers are peanut oil, olive oil, sesame oil and water. Similarly, thecarrier or diluent may include a time delay material such as glycerylmonostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositionscan be used. For example, if a solid carrier is used, the compositionsmay take the form of tablets, capsules, powders, troches or lozenges,prepared by standard pharmaceutical techniques. If a liquid carrier isused, the preparation may be in the form of a soft gelatin capsule, asyrup or a liquid suspension. Suppositories may be prepared in aconventional manner.

The compounds of Formula I are present in an amount sufiicient to treatinflammation. Advantageously, the composition will contain the activeingredient, in an amount of from about 1 mg. to 100 mg. per kg. bodyweight per day (50 mg. to 7 g. per patient per day), preferably fromabout 2 mg. to 50 mg./kg. body weight per day (100 mg. to 3 g. perpatient per day).

The preferred method of treatment comprises internal administration to apatient (animal or human), a compound of Formula I, admixed with anon-toxic pharmaceutical carrier such as exemplified above. Thecompounds of Formula I will be administered in an amount of from 1 mg.to 100 mg./kg. body weight per day preferably from about 2 mg. to about50 mg. per kilogram body weight per day and especially from 4 mg. to 20mg./kg. body weight per day. The most rapid and effectiveanti-inflammatory effect is obtained from oral administration of a dailydosage of from about 4 to 20 mg./kg. per day. It should be understood,however, that although preferred dosage ranges are given, the dose levelfor any particular patient depends upon the activity of the specificcompound employed. Also many other factors that modify the actions ofdrugs will be taken into account by those skilled in the art in thetherapeutic use of the medicinal agents of Formula I; for example, age,body weight, sex, diet, time of administration, route of administration,rate of excretion, drug combination, reaction sensitivities, andseverity of the particular disease.

The compounds of the invention may be produced utilizing the followingstarting materials:

x (1-3) Members of this class such as and X=hydrogen, alkyl, halogen,haloalkyl, N0 alkylsulfonyl, alkylsulfinyl, aryloxy, aralkyl,carboalkoxy and acylaminomethyl;

Y and R are as defined above.

An oxidizing agent such as potassium permanganate is added to thesulfide; S0 added; the mixture filtered;

concentrated in vacuo to a residue.

Hal=chloro or fiuoro; X, Y and R are as defined in (a) above.

atmosphere of hydrogen.

OCH2

and further treatment with an alkylating agent results in the productionof those compounds wherein Carboxylation of the starting materials ofthe formula:

X (l-IDH prepared in accordance with section (a), (b), (c) and (d)proceeds as follows:

COOH OOOH X is hydrogen, alkyl, halogen, haloalkyl, N acylamino,

alkylmercapto, alkylsulfonyl, alkylsulfinyl, acyl, aryloxy, aryl,aralkyl, carboalkoxy and acylaminomethyl.

Y, A, R: and R are as defined above.

An economical method for the carboxylation of the starting material witha carbonate such as potassium carbonate in a high pressure C0atmosphere; heat is applied; the mixture cooled; added to water;filtered; the filtrate is acidified to yield the carboxylated product.

In addition carboxylation may be effected by the use of the Grignardreagent with carbon dioxide in dry ether, followed by hydrolysis.Furthermore, the technique known as the Wanklyn reaction may be employedin this regard.

EXAMPLE 1 Preparation of 5-fluoro-2-thienyl-4'-hydroxyphenylsu1fide To2fluorothiophene (0.1 m.) in ether at 20 C. is added n-butyl lithium(0.1 m.), the mixture stirred one hour, (p-hydroxyphenyl)-disulfide (0.1m.) added carefully, allowed to stir one hour, refluxed gently foranother hour, cooled, water added cautiously and the layers separated.Chromatography (silica gel using an ether-petroleum ether system (v./v.0-70% ether as eluant) yields S-fiuoro-Z-thienyl 4'-hydroxyphenylsulfide.

When 2 chlorothiophene, 2 bromothiophene, thio phene, 2-methylthiophene,2-benzylthiophene, z-phenylthiophene, Z-methylmercaptothiophene,3-fluorothiophene, 2 (and 3) methylsulfonylthiophene, 2,5dimethylthiophene, 2,3,S-trimethylthiophene, furan, 2 (and 3)fluorofuran, 2 (and 3) chlorofuran, 2-bromofuran, 2,3,5-trimethylfuran,2-phenoxyfuran, Z-nitrofuran, Z-trifluoromethylfuran, or2,5-dichlorothiophene are used in place of 2-fluorothiophene in theabove reaction, the corresponding hydroxyphenyl sulfides are obtained.

It may be further noted that the cyclopentadienyl moiety may be employedin the above reaction in place of the thiophenes and furans exemplifiedabove. Representative members of this class include:

2-fiuorocyclopenta(2,4)-dienyl; 3-methylcyclopenta(2,4)-

dienyl; and, ethoxycyclopenta(2,4)-dienyl.

6 EXAMPLE 2 Preparation of 5-fluoro-2-thienyl-4'-hydroxyphenyl sulfoneTo a solution of 5-fluoro-2-thienyl 4'-hydroxyphenyl sulfide (0.1 m.) in1:1 acetic and acid-acetone is added a 3% aqueous solution of potassiumpermanganate (20% excess over theoretical) dropwise and the mixtureallowed to stir several hours. Sulfur dioxide is added in a slow streamuntil all excess permanganate is destroyed and the mixture filtered,concentrated in vacuo, to a residue. The residue is taken up inchloroform, filtered, and concentrated to 5-fiuoro-2-thienyl4-hydroxyphenyl sulfone and then purified via column chromatography.

It shall be readily apparent to one skilled in the art that utilizingthe various substituted thiophenes contemplated by the invention such asthose set forth in Example 1, in place of the fluorothiopheneillustrated above shall result in the preparation of the correspondingsubstituted thienyl-4-hydroxyphenyl sulfones. For example when 2-chlorothiophene, thiophene; (Z-methylthiophene); (2-acetylthiophene);(2-benzylthiophene); and 2-methylmercaptothiophene hydroxyphenylsulfideare oxidized in accordance with the reaction illustrated above, thefollowing phenolic materials are obtained, respectively: S-chloro-Z-thienyl 4-hydroxyphenyl sulfone; 2-thienyl 4-hydroxyphenyl sulfone;5-methyl-2-thienyl-4'-hydroxyphenyl sulfone; 5-chloro-2-thienyl4'-hydroxyphenyl sulfone; S-benzyl-2-thienyl 4'-hydroxyphenyl sulfone;S-methylsulfonyl- 2-thienyl-4-hydroxyphenyl sulfone.

With the methylmercapto-substituted thienyl 4-hydroxyphenyl sulfide,excess is used to account for oxidation of both sulfur atoms.

EXAMPLE 3 Preparation of p-benzoyloxy-N-(Z-thienyl)-acetanilide Amixture of 2-acetamin0thiophene (10 g.), finely powdered potassiumcarbonate (5 g.), benzyl p-iodophenyl ether (20 g.), cuprous iodide (0.5g.), and nitrobenzene (50 ml.) is refluxed gently under a nitrogenatmosphere for 20 hours, the mixture steam distilled, the residue takenup in chloroform washed with water, dried, concentrated in vacuo, andthe residue chromatographed on a silica gel column (10-100%ether-petroleum ether) to yield pbenzyloxy-N-(2-thienyl)-acetanilide.

It should be noted that S-substituted Z-acetaminothiophenes and furansmay also be employed in the above process including the substituentsindicated at Example I.

It should be noted that benzyl m-iodophenyl ether is employed in placeof the p-isomer when a 4-substituted salicylic acid is ultimatelydesired.

EXAMPLE 4 Preparation of p-benzyloxyphenyl 2-thienyl ether A mixture of2-bromothiophene (0.15 m.); p-benzyloxyphenol (0.18 m.), poweredanhydrous potassium carbonate (6.9 g.) and copper bronze (0.2 g.) isheated at 210 C. for two hours, cooled, excess alkali added, the mixtureextracted well with ether and benzene, the combined extracts dried wellover anhydrous magnesium sulfate, filtered and concentrated.Distillation under reduced pressure-or chromatography (silica gel usingan etherpetroleum ether system) yields p-benzyloxyphenyl 2-thienylether.

The above reaction is not only applicable to the substituted thiophenesof this invention containing a 2-bromo group, but may be employedutilizing halo furans and pyrroles. It should be noted thatm-benzyloxyphenol is used in place of p-benzyloxyphenol when ultimatelya 4- substituted salicylic acid is desired.

7 EXAMPLE Preparation of p-hydroxy-N-(2-thienyl)acetanilide A mixture ofp-benzyloxy-N-(2-thienyl)-acetani1ide (0.01 m.), 5% Pd/c (2 g.) andethanol (50 ml.) is shaken in a 40 p.s.i. hydrogen atmosphere at roomtemperature until the theoretical amount (0.01 m.) of hydrogen has beenabsorbed. The mixture is filtered and the solvent removed in vacuo toyield p-hydroxy-N-(Z-thienyl) acetanilide.

When the benzyl ethers of Examples 3 and 4 are treated accordingly, thecorresponding phenols are obtained.

EXAMPLE 6 Preparation of p-hydroxyphenyl 2-thienyl ether To a cold (60)mixture of p-benzyloxyphenyl 2- thienyl ether (0.03 m.) and methylenechloride (50 ml.), which is stirred and protected from moisture, isadded boron tribromide (0.01 m.) and the resultant mixture allowed towarm slowly to room temperature. After stirring several hours, a minimumof aqueous sodium hydroxide is added to hydrolyze the complex. Themixture is then acidified with 2% hydrochloric acid and the layersseparated. The methylene chloride mixture is dried, filtered,concentrated in vacuo, and the residue chromatographed on silica gelusing an ether-petroleum ether system as eluant to yield p-hydroxyphenyl2-thienyl ether.

When the ethers of Examples 3 and 4 are reacted with boron tribromide,the corresponding phenols are obtained.

EXAMPLE 7 Preparation of 5-(5'-fluoro-2-thienylsulfonyl) salicyclic acidAn intimately ground mixture of 2- fiuoro-5(p-hydroxyphenyl)thiophene (5g.) and anhydrous potassium carbonate g.) is heated at 100 in a1200-1400 p.s.i. carbon dioxide atmosphere for 8 hours. The mixture iscooled, added to water (300 ml.), allowed to stir, filtered, and thefiltrate acidified with dilute hydrochloric acid to yield5-(5-fluoro-2-thienylsulfonyl)salicylic acid.

Purification may be effected via recrystallization or 'viachromatography of the methyl ester.

When the phenols, of Examples 1, 2, 5, and 6 are used in the aboveprocedure, the corresponding salicylic acid is obtained.

A representative list of salicyclic acids are as follows:

5-(2-pheny1-5'-cyclopenta(2,4) dienyl-thio-salicylic acid 5-(5'-fluoro2'-cyclopenta(2,4)dienylsulfinyl)salicylic acid5-(2'-mercapto-4-cyclopenta(2,4) dienyl sulfinyl)-salicylic acid 5(5'-fluoro-4'-thienylsulfinyl)-salicylic acid 4(3-methyl-5'-thienylsulfinyl) salicylic acid4(2-methoxy-5'-thienylsulfonyl)salicylic acidN-(5'-mercapto-2-thienyl)-3-carboxy-4-hydroxyacetanilideN-(4'-methyl-2-furyl)-3-carboxy 4-hydroxyacetanilide5-(5-fiuoro-2'-thienylsulfonyl) -salicylic acid5-(5'-methyl-2'-furylsulfonyl)-salicylic acid5-(5-chloro-2'-thienylthio)-salicylic acid5-(1'-(2',4-cyclopentadienyl)-thio)-sa1icylic acid3-carboxy-4-hydroxy-N-(2'-( 1-methylpyrryl)-acetanilide4-(5'-fluoro-2'-thienyloxy)-salicylic acid5-(5-trifluoromethy1-2-thienylthio)-salicylic acid4-carboxyl-3-hydroxy-N-(3-thienyl)-acetanilide5-(5'-methylsulfonyl-2-thienylsulfonyl)-salicylic acid5-(5-fluoro-2-thienyloxy)-salicylic acid3-carboxy-4-hydroxy-N-(Z-thienyl)-acetanilide 8 EXAMPLE 8 Preparation ofmethyl 5-(5'-cyano-2-thienylthio) salicylate A mixture of methyl5-(5'-bromo-2'-thienylthio) salicylate (0.02 m.), cuprous cyanide (0.03m.), and N- methyl-pyrrolidone is de-aerated, covered with a nitrogenatmosphere and heated slowly to C., the mixture is kept at thistemperature for 3 hrs., allowed to cool, partitioned between benzene-7%hydrochloric acid containing ferric chloride (0.03 m.), the benzenelayer then separated, dried, concentrated and the residuechromatographed on a silica gel column using an ether-petroleum ethersystems as eluant (v./v. 580% ether) to yieldmethyl(5-5'-cyano-2'-thienylthio)salicylate.

EXAMPLE 9 Preparation of 5-(5-fluoro-2'-thienylsulfinyl)- salicyclicacid A stirred mixture of 5-(5'-fluoro-2'-thienylmercapto)- salicylicacid (0.01 m.) in acetone-methanol (1:1) is cooled to 5, and sodiummetaperiodate (0.01 m.) in a minimum of water is added. Whenprecipitation of sodium iodate is complete, the mixture is allowed towarm to room temperature, filtered, and the filtrate concentrated invacuo. The residue is taken up in chloroform, the chloroform mixturefiltered, and the filtrate concentrated in vacuo to5-(5'-fiuoro-2'-thienylsulfinyl)salicylic acid.

It should be noted that this procedure may be carried out on the phenoland the resulting sulfinylphenol carbonated as in Example 7 to yield thesame product.

When the S-(5'-methylthiothienyloxy)-, 5-(5'-methylthiothienylthio)-, 5(5-methylthiothienylthio-, 5 (5- methylthiofuryloxy)-,4-(5'-methylthiofurylthio) -salicylic acids, etc., are oxidized asabove, the corresponding methylsulfinyl analogs are obtained. With thosecontaining two oxidizable groups, e.g.5-(5'-methylthiothienylthio)-salicylic acid, two equivalents of sodiummetaperiodate are needed.

EXAMPLE 10 Preparation of methyl 2-acetoxy-5(5'-ibromomethyl-2'-thienyloxy)-benzoate A mixture of methyl2-acetoxy-5(5'-methyl-2'-thienyloxy)benzoate (0.05 m.),N-bromosuccinimide (0.05 m.), carbon tetrachloride (500 ml.) anddibenzoyl peroxide (0.002 m.) is refluxed gently for 3 hrs. and cooled.The succinimide is removed by filtration, and the solvent removed invacuo to yield methyl 2-acetoxy-5(5'-bromomethyl-2-thienyloxy) benzoate.

It will be appreciated by the skilled artisans that substituted furansmay be employed in the practice of the above process in place of thethiophene moiety.

EXAMPLE 11 Preparation of methyl 5-(5-hydroxymethyl2'-thienyloxy)salicylate A mixture of methyl2-acet'oxy-5-(5'-bromomethyl-2- thienyloxy)benzoate (0.01 m.), silveracetate (0.01 m.) and acetic acid (30 ml.) is heated gently for threehours, cooled, filtered, and the filtrate concentrated in vacuo to aresidue of crude methyl2-acetoxy-5-(S-acetoxymethylthienyloxy)-benzoate. Anhydrous methanol (50ml.) and p-toluene sulfuric acid (0.1 g.) is added and the mixtureheated for three hours, concentrated, distributed betweenwater-chloroform, the chloroform layer dried, concentrated, and thecontents chromatographed on a silica gel column using an ether-petroleumether system (v./v. 0100% ether) as eluant, yielding methyl5-(5'-hydroxymethyl-2'-thienyloxy salicylate.

When potassium thiolacetate is used in place of silver acetate in theabove reaction; methyl 5-(5-mercaptomethyl 2'-thienyloxy)salicylate isobtained.

9 EXAMPLE 12 Preparation of methyl 5-(5-dimethylaminomethyl-2'-thienyloxy) salicylate Methyl 2-acetoxy-5(5'-bromomethyl 2'thienyloxy)- benzoate (0.02 m.) is heated in methanolic dimethylamine.The solvents removed in vacuo and the residue taken up in 1.0 Nhydrochloric acid, filtered, basified, and the resultant methyl5-(5'-dimethylaminomethyl-2'-thienyloxy) salicylate collected.

When methanolic ammonia is used in place of the dimethylamine in theabove reaction, the corresponding 5 -aminomethyl salicylate is obtained.

EXAMPLE 13 Preparation of methyl 5-(5-methoxymethyl-2-thienylsulfonyl)-salicylate Methyl Z-acetoxy-S(5'-bromomethyl 2thienylsulfonyl benzoate (0.01 m.) is added to a stirred solution ofsodium methoxide (0.02 m.) in anhydrous methanol. The mixture isrefluxed gently for one hour, cooled, dilute hydrochloric acid added toneutralize the mixture, and the solvents removed in vacuo. The residueis chromatographed on a silica gel column using an ether-petroleum ethersystem (v./ v. 80% ether) as eluant to yield methyl5-methoxymethyl-2'-thienylsulfonyl) -salicyl ate.

When potassium methylmercaptide is used in place of sodium methoxide,methyl 5-(5'-methylthiomethyl-2- thiensulfonyl)-salicylate is obtained.

EXlAMPLE 14 Preparation of methyl 5-(5-carbamyl-2.'-thienylsulfonyl)-salicylate A mixture of methyl5-(5'-cyano-2'-thienylsulfonyl)- salicylate (0.02 m.) and polyphosphoricacid (50 ml.) is heated on a steam cone for 1 hour. The mixture iscooled, added to water and the aqueous mixture extracted withchloroform. The chloroform layer is dried, filtered, and thenconcentrated in vacuo to yield methyl 5-(5-carbamyl-2'-thienylsulfony1)-silicylate which may be purified via columnchromatography or recrystallization of the corresponding salicylic acid.

EXAMPLE 15 Preparation of N-(5'-carboxy-2-thienyl)-3-carboxy-4-l1ydroxy-acetanilide To a mixture of N-(5'-carbomethoxy-2'-thienyl)-3-carboxy-4-hydroxy-acetanilide (0.01 m.) and methanol (100 ml.) is addedwith stirring sodium hydroxide (0.06 m.) and water (15 ml.). Theresulting mixture is stirred overnight at room temperature, diluted withwater (200 ml.), filtered and the filtrate acidified with 2.5 Nhydrochloric acid and the N-(5-carboxy-2.-thienyl)-3-carboxy-4hydroxy-acetanilide collected.

EXAMPLE 16 Preparation ofZ-acetoxy-S-(5'-chloro-2'-thienylsulfonyl)benzoic acid To a mixture of5-(5'-chloro-2-thienylsulfonyl)salicylic acid (0.04 m.) in anhydrouspyridine (15 ml.) is added acetic anhydride (28 ml.) and the resultantmixture heated on the steam cone for 1.5 hrs. The mixture is kept freefrom moisture during this time. On cooling, the mixture is added to astirred 500 ml. portion of water. The aqueous system is then extractedwell with chloroform, the chloroform extracts washed with 1 Nhydrochloric acid, water, and then dried over anhydrous magnesiumsulfate. Concentration of the filtered solution yieIdsZ-acetOxy-S-(5'-chloro-2'-thienylsulfonyl) -benzoic acid.

When propionic or butyric anhydride is used in place of acetic anhydridein the above example, the corresponding propionoxy or butyroxy compoundsare obtained.

10 EXAMPLE 17 Preparation of methyl2-carboxy-4-(5-fluorothienylthio)-phenyl carbonate To a mixture of5-(5-fluorothienylthio) salicylic acid (0.01 m.), dimethylaniline (0.02m.) and benzene (30 ml.) is added methyl chloroformate (0.011 In.) overone hour with constant shaking and cooling. When the odor of thechlorocarbonate is essentially absent, hydrochloric acid (1 N, ml.) isadded and the mixture filtered. The benzene layer is then separated,dried, filtered, and the solvent removed in vacuo to yield methyl2-carboxy-4- (5'-fiuorothienylthio)-phenyl carbonate.

EXAMPLE 18 Preparation of 2(3-carboxy-4'-methoxy phenoxy)-5-fluorothiophene To a mixture of 2(3'-carboxy-4'-hydroxy phenoxy)-5-fiuorothiophene (0.01 m.) in 2 N sodium hydroxide solution at 70 isadded dimethyl sulfate (0.10 m.) in small portions over ten hours, themixture being kept basic throughout the addition. Water is added, themixture filtered, the filtrate acidified and 2(3'-carboxy-4'-methoxyphenoxy)5-fluorothiophene collected.

The esters of the invention may be obtained by utilizing a diazomethanereagent. Alternatively, esterification may be effected with anappropriate alcohol in an inert solvent in the presence of an acidcatalyst such as an aryl sulfonic acid. Further exemplification ofesterification procedures is indicated in the following three examples:

EXAMPLE 19 Preparation of methyl Z-acetoxy5(5-fluoro-2'-thienylsulfonyl)-benzoate Diazomethane in methylenechloride is added to an ice cooled mixture ofZ-acetoxy-S-(5'-fluoro-2'-thienylsulfonyl)-benzoic acid in methylenechloride until nitrogen evolution ceases and the color of diazomethanepersists. The solvent is then removed in vacuo to yield methyl 2-actoxy-5- 5'-fiuoro-2-thienylsulfonyl) -benzoate.

When other diazo compounds are used in place of diazomethane in theabove example, for example diazoethane, phenyldiazomethane, etc., thecorresponding esters are obtained.

When the acids of Examples 7, 9', 15, 16, 17 and 18 are treated thusly,the corresponding esters are obtained.

EXAMPLE 20 Preparation of methyl 5(5'-fluoro-5-thienylsulfonyl)-salicylate 5-(2-fiuoro-5-thienylsulfonyl)salicylic acid (0.01 m.) isadded to a solution of anhydrous methanol (25 ml.) containing ca. 100mg. of anhydrous sulfuric acid. The resultant mixture is heated undergentle reflux, the solvent removed in vacuo and the residue partitionedbetween chloroform-dilute sodium bicarbonate solution and the layersseparated. The chloroform layer is dried over anhydrous sodium sulfate,filtered and evaporated to leave methyl 5 5'-fiuoro-2'-thienylsulfonylsalicylate.

When ethanol, propanol, isopropanol, or butanol, is used in place ofmethanol in the above reaction, the corresponding ester is produced.

When the salicylic acids of Example 7 are used in place of5(2-fluoro-5-thienylsulfonyl)salicylic acid in the above example, thecorresponding esters are obtained.

EXAMPLE 21 Preparation of phenyl-S-(5'-fluoro-2'-furylsulfonyl)-salicylate To a mixture of polyphosphate esters (PLP.E.) chloroform isadded one equivalent each of 5-(5-fluoro-2'- fury1sulfonyl)salicylicacid and phenol, and the resultant mixture is heated gently for 30minutes. The chloroform mixture is cooled, washed with dilutebicarbonate solution. The chloroform layer is then dried, filtered andevaporated in vacuo to yield phenyl (5fiuoro-2-furylsulfon-ylsalicylate.

When the salicylic acids of Example 7 are used in the above reaction,the corresponding phenyl esters are obtained.

EXAMPLE 22 Preparation of 5(5'-fluoro-2-thienylsulfonyl)salicylanilide Amixture of phenyl 5-(5'-fiuoro-2'-thienylsulfonyl) salicylate (0.1 m.);aniline (0.1 m.) and l-methylnaph' thalene (50 ml.) are heated slowly to230 C., kept at this temperature until phenol has stopped distilling.Charcoal (2 g.) is then added and then 20 ml. additionalmethylnaphthalene added. The mixture is heated for min., filtered hot,and cooled. The collected anilide is then recrystallized yielding pure5(5'-fiuoro-2-thienylsulfonyl) salicylanilide.

EXAMPLE 23 Preparation of 5(5-chloro-2-furylsulfinyl)salicylamide Amixture of methyl 5-(5'-chloro 2'-furylsulfinyl) salicylate andconcentrated ammonium hydroxide (five-fold excess) is heated at 100 C.in a sealed tube for six hours. After cooling, water is added and the5(5-chloro 2'-furylsulfinyl) salicylamide collected.

When monomethylamine, dimethylamine, ethylamine, diethylamine,morpholine, piperidine, etc. are used in place of ammonium hydroxide,the corresponding amides are obtained.

EXAMPLE 24 Preparation of methyl 5-(5-methoxyfurylsulfonyl)salicylate Amixture of 10 g. of methyl 5(5-bromo-2-furylsulfo- 11yl)salicylate and125 ml. of 2.5 M sodium methoxide in absolute methanol is heated for 30min. at ca. 90 in a stoppered bottle, the excess methanol removed invacuo, dilute hydrochloric acid added and the mixture extracted withchloroform. Concentration of the chloroform solution yields methyl5-(5'-methoxyfurylsulfonyl)salicylate.

When an equivalent amount of sodium benzylate in methanol is used inplace of sodium methoxide, the 5'-benzyloxy analog is obtained.

When the salicylates of the invention are reacted with silver acetate inacetic acid, the corresponding acetoxy analog are obtained.

When reacted with excess methanolic dimethylamine, the S-dimethylaminoanalog is obtained.

EXAMPLE 25 Preparation of sodium 3-carboxy-4-hydroxy-N-(2'-(1'-methylpyrryl acetanilide Solutions of3-carboxy-4-hydroxy-N-(2'(1-methylpyrryl)acetanilide in methanol andsodium hydroxide (1 equiv.) in water are mixed, heated for solution,filtered, and the filtrate concentrated in vacuo to obtain sodium3-carboxy-4-hydroxy-N-(2-(1-methylpyrryl)acetanilide.

When potassium hydroxide is used in place of sodium hydroxide in theabove example, the corresponding potassium salt is obtained.

When two equivalents of the above bases are used, the correspondingdisodioand dipotaSsio-salts are obtained.

EXAMPLE 26 Preparation of diethylaminoethanol salt of5-(l'-2'4-cyclopentadienyl)-thio)-salicylic acid N,N-diethylethanolamine(0.001 m.) in ether (5 ml.) is added to a stirred solution of5-(l'-(24'-cyclopentadien- 4 3 X {B g- A 3. wherein A is S, S0 or S0 Yis S, R2 is H, R is H,

X is H or halogen, and R is hydroxy,

with the proviso that the OR; group and the 0 II 1-C-R group are alwaysortho to one another.

2. The method of claim 1 wherein the compound is 5- 5-fiuoro-4-thienylsulfinyl salicylic acid.

3. A pharmaceutical preparation in dosage unit form adapted foradministration to obtain an antiinflammatory effect, comprising apharmaceutical diluent and, per dosage unit, an antiinflammatoryeffective non-toxic amount within the range from about 50 to about 7,000milligrams of a compound of structural formula:

wherein A is S, S0 or S0 Y is S,

R2 is H,

R3 iS H,

X is H or halogen, and

R is hydroxy,

with the proviso that the -OR group and the 0 ll -c-R1" group are alwaysortho to one another.

4. A pharmaceutical preparation in accordance with claim 3 in a formadapted for oral administration.

No references cited STANLEY J. FRIEDMAN, Primary Examiner U.S. Cl. X.R.

424230, 248, 274, 275, 285, 300, 304, 308, 317, 325; 260-247.1, 247.2 B,247.5 R, 247.7 H, 332.2 A, 347.3, 347.4, 465, 469, 470, 471, 473, 476,478, 515, 516, 518, 520, 559 S, 559 H UNITED STATES PATENT OFFICECERTIFICATE OF CORRECTIQN Patent No. 3,657,432 Dated April 18, 1972Inventofls) 'Ifsung-Ying Shen et a1.

It is certified that error appears in the above-identified patent andthat said Letters Patent} are hereby corrected as shown below:

In column 2, line 10, the word "methylsulfony" should be--methylsulfonyl--; v V v In column 2, line 25, the word "ca'rbomethyl"should be -carbomethoxy---;

In column 3, line 60, the right hand ring of the structure should read Q0H In column 5, line 30, from left he w COOHII In column 7, line 60,thenumber "4" should be --5---;

hiensulf'onyl) should nd formula, delete and In column 9, line 30, theword "t be -thienylsulfonyl) Signed and sealed this 26th day ofSeptember 1972.

(SEAL) Attest ROBERT GOTTSCHALK Commissioner of Patents EDWARDM.FLE'I'CHER,JR. Attesting Officer

